Integrating Twin, Molecular, and Developmental Approaches to Understanding Alcohol Misuse: This application requests funding for a five year K02 award, with the overarching goal of developing an interdisciplinary program of research aimed at advancing our understanding of how genetic influences impact the development of alcohol use disorders. This will be accomplished by integrating findings across twin studies, gene identification projects, and longitudinal, community-based samples. The research plan has three broad aims: (1) To use twin studies to characterize the nature of genetic and environmental influences on alcohol use and related disorders, with focus on (a) studying the changing influence of genetic effects as a function of the environment and across development, and (b) understanding how genetic influences impact the phenotypic spectrum of risk associated with alcohol use disorders. The second aim (2) is to identify genes involved in alcohol use and related phenotypes. The third aim (3) is to characterize the risk associated with identified genes using community-based samples of individuals studied longitudinally, to test how the effect associated with specific genes may change across development and in conjunction with specific environmental factors. These aims will be accomplished by integrating data across several of my funded projects: two population-based twin samples, FinnTwin12 and the Virginia Adult Twin Study of Psychiatric and Substance Use disorders;two gene identification projects: the Collaborative Study on the Genetics of Alcoholism and the Irish Affected Sib Pair Study of Alcohol Dependence;and three longitudinal, community-based samples: the Child Development Project, a study of ~500 children followed annually from age 5-25;the Mobile Youth Study, an on-going study of African-American children ages 10-18 from high-risk, impoverished neighborhoods;and the Avon Longitudinal Study of Parents and Children, an epidemiological cohort of ~10,000 children enrolled from a geographically-limited region in the UK, and assessed repeatedly (minimally yearly) prenatally through young adulthood. Accordingly, this project integrates findings across a number of research approaches, using results from twin studies about the nature of genetic influences (Aim 1) to develop hypotheses to test about the risk associated with specific genes (identified in Aim 2) in longitudinal, community samples (Aim 3). Together, these studies will synergize to advance our understanding of how genetic and environmental factors come together to influence to the development of alcohol problems. To inform my ability to conduct the proposed analyses, focused career development is proposed in two new content areas: (i) early childhood risk factors for alcohol problems, and (ii) racial differences in risk factors for alcohol problems, and two methodological areas: (i) GWAS methodology, and (ii) longitudinal data analyses. These stem directly from my funded projects and represent expansions to my current areas of expertise in alcohol research. PUBLIC HEALTH RELEVANCE: The complexity of the genetics of alcohol dependence necessitates a variety of research approaches. This project integrates analyses from twin studies, used to characterize the nature of genetic influences on alcohol- related phenotypes;molecular genetic studies, aimed at gene identification;and community-based samples, used to characterize the risk associated with specific genes across development and as a function of the environment. Understanding how genetic and environmental factors interact across development will be critical to develop more effective, tailored programs of prevention and intervention.